US20170233826A1 - Mrna and/or protein of ercc1 isoform 3 for use in diagnosing a resistance against a therapeutic agent and method for diagnosing a resistance against a therapeutic agent using said mrna and/or protein - Google Patents

Mrna and/or protein of ercc1 isoform 3 for use in diagnosing a resistance against a therapeutic agent and method for diagnosing a resistance against a therapeutic agent using said mrna and/or protein Download PDF

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US20170233826A1
US20170233826A1 US15/511,837 US201515511837A US2017233826A1 US 20170233826 A1 US20170233826 A1 US 20170233826A1 US 201515511837 A US201515511837 A US 201515511837A US 2017233826 A1 US2017233826 A1 US 2017233826A1
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cancer
mrna
therapeutic agent
ercc1
protein
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Siegfried Hauch
Yvonne BOKELOH
Jenny Wagner
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Alere Diagnostics GmbH
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Adnagen GmbH
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6804—Nucleic acid analysis using immunogens
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • CTC circulating tumor cells
  • AdnaTest® which combines immunomagnetic capturing followed by a molecular characterization of such captured cells by means of mRNA profiling, is a useful tool to address such questions.
  • an early identification of a successful therapy is of paramount importance, especially in ovarian cancers where prognosis is already bad.
  • Such method is disclosed e.g. in EP 1 409 727 A2, which is herewith incorporated by reference.
  • Platinum-based therapeutic agents or regimens are the first and most promising choice in the treatment of some forms of cancer, e.g. ovarian cancer after surgery. However, about 20% of the patients already have developed, or are about to develop, resistance against platinum-based therapeutics. Thus, said patients no longer benefit from these therapeutics or these regimen.
  • ERCC1 is a DNA repair gene which was regarded for a long time as a tissue biomarker to provide predictive information about a resistance to platinum-based therapeutic agents.
  • immunohistochemical detection of ERCC1 protein in tissue lacks specificity and was unsuitable for correct prediction of resistance to platinum-based therapeutic agents.
  • ERCC1 isoforms 2, 3 and 4 are non-functional in nucleotide excision repair capacity. Consequently, it was assumed that they are unsuitable for use as a biomarker.
  • only ERCC1 isoform 1 was found to be suitable to be used as a biomarker (see Friboulet L. et al., Cell Cycle, vol.
  • ERCC1 isoforms 1 and 4 are highly similar which means that it is not possible to date to specifically detect isoform 1 expression without codetection of isoform 4 expression.
  • the expression of ERCC1 isoforms 1 and 4 is time and tissue-specific which means a detection of isoform 1 is afflicted with a large inter-tissue variation and is error-prone because of interference with isoform 4 codetection.
  • ERCC1 isoform 3 protein for use according to claim 1 ERCC1 isoform 3 mRNA for use according to claim 2 , the method for diagnosing a resistance against a therapeutic agent according to claim 3 and the use of ERCC1 isoform 3 protein and/or mRNA as biomarker according to claim 4 .
  • the dependent claims refer to preferred embodiments thereof.
  • ERCC1 isoform 3 protein and/or mRNA is suggested for use in diagnosing a resistance against a therapeutic agent.
  • the isoform 3 of ERCC1 is also known as “ERCC1 201” and the protein has the identifier P07992-3 at the “Swiss-Prot” protein database (see www.uniprot.org).
  • ERCC1 isoform 3 mRNA any mRNA is understood which codes for the ERCC1 isoform 3 protein having the identifier P07992-3 at the “Swiss-Prot” protein database.
  • ERCC1 isoform 3 protein production in a cell correlates with resistance to therapeutic agents like platinum-based therapeutic agents.
  • the finding is surprising because the isoform 3 of ERCC1 is known not to be involved in the development of resistance to therapeutic agents.
  • the advantage of ERCC1 isoform 3 protein and/or mRNA is that it is structurally considerably different to the other isoforms of ERCC1 and thus can be determined without the problem of codetection of isoforms 1, 2 and/or 4. Consequently, ERCC1 isoform 3 is a more reliable marker for detecting resistances compared to e.g. ERCC1 isoform 1.
  • a method for diagnosing a resistance against a therapeutic agent comprises or consists of the steps of
  • the therapeutic agent may be a cancer therapeutic agent, preferably selected from the group comprising or consisting of platinum-based cancer therapeutic agents, radiation-based cancer therapeutic agents and DNA-destructive cancer therapeutic agents.
  • the use of ERCC1 isoform 3 protein and/or ERCC1 isoform 3 mRNA as biomarker for resistance to a therapeutic agent is suggested.
  • the biomarker is a biomarker used for detecting a resistance to a cancer therapeutic agent, more preferably a platinum-based cancer therapeutic agent, a radiation-based cancer therapeutic agent and/or a DNA-destructive cancer therapeutic agent.
  • Diagnosing may be done on a liquid sample from a human body and/or a tissue sample from a human body, preferably an isolated liquid sample from a human body and/or a tissue sample from a human body (in-vitro-method).
  • the sample may comprise or consist of a body fluid (e.g. peripheral blood, sputum, ascites, lymph, urine and/or bone marrow).
  • the sample may also comprise or consist of a biopsy material (e.g. a biopsy material from a primary tumor).
  • the cancer may be selected from the group comprising or consisting of a solid cancer, preferably ovarian cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, bladder cancer, gastric cancer, colon cancer, testicular cancer and neck cancer. Particularly preferred is ovarian cancer. Most preferably diagnosing regards ovarian cancer after surgery.
  • Diagnosing the resistance may comprise a step of isolating circulating tumor cells, preferably by a multi-antibody capturing method, and a step of determining the level of expression of ERCC1 isoform 3 protein and/or ERCC1 isoform 3 mRNA in the isolated circulating tumor cells.
  • the isolation of the circulating tumor cells may be performed on a liquid sample from a human body and/or a tissue sample from a human body.
  • the isolation of the circulating tumor cells is performed on an isolated liquid sample from a human body and/or a tissue sample from a human body (in-vitro-method).
  • AdnaTest® OvarianCancerSelect/Detect may be used for isolating circulating tumor cells.
  • the step of isolating circulating tumor cells may comprise or consist of the steps of
  • the antibodies and/or antibody derivatives are preferably coupled to at least one magnetic or paramagnetic particle.
  • magnetic force may be used for isolation of said complexes.
  • the antibodies and/or antibody derivatives may be coupled to at least one fluorescent molecule. In this case, fluorescence activated cell sorting can be used for isolation of said complexes.
  • At least one of the two antibodies and/or antibody derivatives may be selected from the group comprising or consisting of GP1.4, MOC-31, Ber-EP-4, HMPV.2, HMEIV.2, 8B6, E29, 10E9 (anti-HER2), 2D3 (anti-EpCAM) anti-cMET, anti-EGFR, anti-cKIT, anti-IGFR and 131-11741.
  • Diagnosing the resistance may comprise the step of
  • measuring in step b) and/or step c) is done by RT-PCR, LCR, NASBA, a hybridisation method and/or a method containing the steps of PCR, digesting of the PCR product with restriction enzymes to fragments and analysis of said obtained fragments.
  • the at least one mRNA, which is different to ERCC1 isoform 3 mRNA may be selected from the group comprising or consisting of mRNAs which are markers for cells of epithelial, mesenchymal or stem cell phenotype, preferably the group comprising or consisting of mRNAs recited in Table 1.
  • Diagnosing the resistance preferably comprises a step of comparing a measured expression level of ERCC1 isoform 3 protein and/or ERCC1 isoform 3 mRNA with a first predetermined value, wherein a measured expression level of ERCC1 isoform 3 protein and/or ERCC1 isoform 3 mRNA above the first predetermined value indicates a resistance against said therapeutic agent.
  • Diagnosing the resistance may comprise the steps of
  • the at least one mRNA, which is different to ERCC1 isoform 3, may be selected from the group comprising or consisting of mRNAs recited in Table 1 (see above).
  • the FIGURE shows the results of the PCR assay validation by ROC curve analysis. Plotted is the sensitivity against the specificity of ERCC1 isoform 3 detection among all ERCC1 isoforms. More than 90% specificity (at 50% sensitivity) is obtained at a fragment concentration of approx. 0.2 ng/ ⁇ l.
  • cDNA was extracted from blood samples of 99 ovarian cancer patients and 21 healthy patients using the AdnaTest OvarianCancerSelect/Detect assay kit. Said cDNA potentially comprises all four isoforms of ERCC1. Subsequently, a fragment concentration analysis regarding the level of ERCC1 isoform 3 was performed using an Agilent 2100 Bioanalyzer (Agilent Technologies).
  • PCR e.g. semi-quantitative PCR
  • PCR is a suitable method amongst others to specifically detect ERCC1 isoform 3 among all ERCC1 isoforms.
  • CTC circulating tumor cells
  • CTC CTC analysis was performed by immunomagnetic CTC enrichment targeting the epitopes of epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1) and subsequently conducting a multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including, in a separate approach, ERCC1 isoform 3 transcripts.
  • EPCAM epithelial cell adhesion molecule
  • MUC1 mucin 1
  • MUC16 mucin 16
  • CTC ERCC1+ ERCC1 isoform 3-positive CTC
  • CTC ERCC1+ ERCC1 isoform 3-positive CTC
  • DFS disease-free survival
  • ERCC1 refers to ERCC1 isoform 3
  • DFS disease-free survival
  • OS refers to overall survival
  • HR hazard ratio
  • Figo refers to the clinical Figo staging
  • pN lymph node stage
  • M refers to metastatic stage
  • G refers to Grading
  • RTB residual tumor burden
  • CTC pre refers to circulating tumor cells before therapy
  • CTC post refers to circulating tumor cells after therapy
  • CTC (ERCC1+) refers to CTC which overexpress ERCC1 isoform 3 mRNA. Platinum resistance (log.
  • ERCC1 isoform 3 in CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance as well as for providing a prognosis for a disease-free survival.

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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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US15/511,837 2014-09-18 2015-09-16 Mrna and/or protein of ercc1 isoform 3 for use in diagnosing a resistance against a therapeutic agent and method for diagnosing a resistance against a therapeutic agent using said mrna and/or protein Abandoned US20170233826A1 (en)

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EP14185247.5 2014-09-18
EP14185247 2014-09-18
PCT/EP2015/071170 WO2016042009A1 (en) 2014-09-18 2015-09-16 Mrna and/or protein of ercc1 isoform 3 for use in diagnosing a resistance against a therapeutic agent and method for diagnosing a resistance against a therapeutic agent using said mrna and/or protein

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EP (1) EP3194616B1 (de)
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WO (1) WO2016042009A1 (de)

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US20200377955A1 (en) * 2017-06-20 2020-12-03 Liquid Genomics, Inc. USE OF CELL-FREE CIRCULATING RNA (cfRNA) EXPRESSION OF PD-L1 AND ERCC1 IN PLASMA TO MONITOR RESPONSE TO THERAPY IN NSCLC

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ATE309393T1 (de) * 2001-09-06 2005-11-15 Adnagen Ag Verfahren zum qualitativen und/oder quantitativen nachweis von zellen
US9702875B2 (en) * 2006-03-14 2017-07-11 Institute Gustave-Roussy Expression of isoform 202 of ERCC1 for predicting response to cancer chemotherapy
WO2007121465A2 (en) * 2006-04-18 2007-10-25 Wellstat Biologics Corporation Detection of proteins from circulating neoplastic cells
EP2233589A1 (de) * 2009-03-19 2010-09-29 Institut Gustave Roussy MSH2 und Adjuvans-Cisplatin-basierte Chemotherapie in nicht-kleinzelligem Lungenkrebs
US20120178094A1 (en) * 2009-09-03 2012-07-12 Peter Kuhn Method for Categorizing Circulating Tumor Cells
CA2814528A1 (en) * 2010-10-14 2012-04-19 Veridex, Llc Methods and kits for the detection of circulating tumor cells in pancreatic patients using polyspecific capture and cocktail detection reagents

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EP3194616A1 (de) 2017-07-26
WO2016042009A1 (en) 2016-03-24
JP7057668B2 (ja) 2022-04-20
JP2021019612A (ja) 2021-02-18
JP2017529074A (ja) 2017-10-05
EP3194616B1 (de) 2020-07-29

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